Schizophrenia is a common, disabling disorder with a lifetime morbid risk of 1%. Its etiology is unknown, but a relatively high heritability (60-70%) is well established. Prior gene mapping efforts have achieved limited success, probably due to the complex genetic etiology. We propose to build on the strengths of linkage analyses and available information about pathogenesis to detect gene/s conferring liability. Specifically, targeting genomic regions identified by linkage analysis and guided by data suggesting dopaminergic (DA) dysregulation in the brains of patients with schizophrenia, we will test positional candidate genes involved in DA neurotransmission. Such a strategy also garners support from family-based association analyses, as we and others have also detected plausible linkage and association with DA genes. To identify liability genes, we will use the results of an in-progress genome scan using 400 affected sib-pairs (ASPs). We will choose approximately 20 positional candidates based on the intersection of information from the genome scan and the neuroscience of DA. These genes will be evaluated through multi-layered analyses involving linkage and linkage I association among a total of 680 ASPs and 930 simplex case-parent trio families. We will utilize selected, informative single nucleotide polymorphisms (SNPs) and haplotypes. Initial results from a US/UK sample will be evaluated in an independent Asian Indian sample. Genes surviving this intense interrogation will be assessed further by functional assays and the available information synthesized. Clinical information and DNA from consenting US participants will be available to the scientific community. This is a competing renewal of grant # MH 56242